In 2009, a global collaboration of scientists, public health agencies, and companies raced to make a vaccine against a pandemic influenza virus, but most of it wasn't ready until the pandemic had peaked. Now, researchers have come up with an alternative, faster strategy for when a pandemic influenza virus surfaces: Just squirt genes for the protective antibodies into people's noses. The method—which borrows ideas from both gene therapy and vaccination, but is neither—protects mice against a wide range of flu viruses in a new study.
James Wilson, a leading gene therapy researcher at the University of Pennsylvania, credits the idea to a meeting with Bill Gates in April 2010. Wilson had studied whether a harmless gene therapy tool called adeno-associated virus (AAV) can serve as a gene delivery vehicle to treat inherited diseases like cystic fibrosis and hemophilia. Gates, whose foundation focuses on global health, "asked me whether the AAV-mediated approach could be used in the context of a pandemic or emerging infection," Wilson recalls.
Wilson was intrigued by the idea. Building off of animal studies done by AIDS researchers as well as his own work with cystic fibrosis, he wondered whether a specially engineered AAV could deliver the genes encoding influenza antibodies to the cells that line people's airways. If it worked, these so-called epithelial cells would produce influenza antibodies right at the site where the virus attempts to establish an infection.
One key problem from the outset was deciding which antibody to make, because there are many different flu strains; a one-size-fits-all solution would be ideal. Then, in a 2011 paper in Science, immunologist Antonio Lanzavecchia at the Institute for Research in Biomedicine in Bellinzona, Switzerland, reported isolating a rare "broadly neutralizing antibody," able to fight off many influenza strains.
Wilson and co-workers engineered AAV to carry the gene for the rare antibody. When they delivered this virus into the noses of mice and ferrets, the animals' epithelial cells produced the desired antibodies; they then "challenged" the animals with a range of dangerous influenza viruses that no single vaccine can outwit, including H5N1, which kills both birds and humans, and the H1N1 that caused the infamous 1918 pandemic. As they report today in Science Translational Medicine, the antibodies provided solid protection against disease in most cases.
"It's an excellent study," Lanzavecchia says, noting that much credit should be given to the researchers who first published a similar experiment with the AIDS virus in 2002. "This is a new application of an approach pioneered by other groups," he says. "The main question is: How do you want to use this approach? Is gene therapy prophylaxis for flu sustainable?"
The problem, he explains, is that the strategy is different from vaccination, in which the body's immune system produces antibodies and remembers how to do so for years or even decades. In this case, AAV acts as a Trojan horse and leads epithelial cells in the airways to make the antibodies; the question is how long they will continue doing so.
Philip Johnson, a molecular virologist at the Children's Hospital of Philadelphia in Pennsylvania who did the earlier work with AAV and antibodies against the simian version of the AIDS virus, showed in a monkey experiment published in Nature Medicine in 2009 that his vector worked for more than a year. In contrast, AAV had petered out in about 3 months in a monkey experiment in Wilson's study. Johnson says a key difference is that he injected into a muscle, which has long-lived cells, whereas Wilson sprayed the vector into the nose. The airway epithelial cells that the method relies on are continuously shed, he notes.
Wilson agrees that 3 months of protection is "not optimal" during an influenza pandemic. He's now working on ways to increase durability and says that his target is 6 months. But the goal is not to make the vector produce antibodies forever, he says. That's in part because of safety concerns. Wilson famously led a gene therapy study with an adenovirus vector that killed a patient, Jesse Gelsinger, in 1999—a major setback for the entire field. Although AAV has never caused harm in a human, there are always unknowns with artificial viral vectors.
Wilson sees his work as a stopgap measure until researchers figure out how to make a vaccine that triggers broadly neutralizing antibodies. But as of now, despite intense efforts, researchers have been unable to design a vaccine that triggers the production of these powerful molecules. "We still have a ways to go," he says, "and until that happens, we'll just keep plugging away at this."